Ricerc@Sapienza

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating
mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In
the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization
and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in
a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin
producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A
is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either
Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production
of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests
that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress
through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the
antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic
instability. Although MODY-2 rarely produces complications, our data revealed the possibility that
MODY-2 impacts genome integrity